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Validation of small molecules preventing TDP-43 aggregation as a therapeutic for Amyotrophic Lateral Sclerosis

Principal Investigator:
  • Marc Shenouda, University of Toronto
  • ALS Society of Canada
  • La Fondation Vincent Bourque

Project Overview

TDP-43 is a protein that behaves abnormally in the motor neurons of 97 per cent of people with ALS. It is usually found in the nucleus, but in people with ALS, it becomes trapped outside in the cytoplasm where it forms aggregates. One theory is that these aggregates are toxic to motor neurons. Therefore, preventing these clumps from forming, or breaking them apart, could be a potential method for treating ALS.

In Dr. Robertson’s lab, Marc Shenouda has been using a computer program that models how compounds fit together with proteins. He has screened 50,000 experimental drugs to look for those that have the most potential to bind to TDP-43 and prevent it from aggregating. He has created a shortlist of 500 drug candidates for further testing.

For this project, Shenouda will test 500 experimental drugs in motor neuron cells in culture to see if they can effectively reduce TDP-43 aggregation and toxicity. He will then take the best candidate compound and test it in a TDP-43 ALS mouse model to see if it can change the course of the disease. Shenouda hopes that this project may discover a potential new treatment for ALS that could someday be tested further in a clinical trial.